# US 10,869,863 B2 · Multi-arm polymeric targeting anti-cancer conjugate

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- Number: US 10,869,863 B2
- Document ID: US10869863B2
- Status: Granted
- Kind: B2
- Application number: 16/300,428
- Filed: 2017-05-15
- Published: 2020-01-02
- Granted: 2020-12-22
- Earliest claimed: 2016-05-16
- Assignees: BrightGene Bio-Medical Technology Co., Ltd.
- Applicants: BrightGene Bio-Medical Technology Co., Ltd.
- Inventors: Jiandong Yuan; Yangqing Huang; Yunsong Song; Fang Yuan
- Web page: https://patentgrep.com/patent/US10869863B2

## CPC

- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- C08G 65/329: with organic compounds
- A61K 47/545: {Heterocyclic compounds (A61K47/558 takes precedence)}
- A61K 47/58: obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- C08G 65/33396: {having oxygen in addition to nitrogen}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed is a multi-arm targeting drug conjugate modified by a water-soluble polymer; the drug conjugate has the structural formula of (III). In formula (III), R is an organic core, POLY is a polymer, L is a multivalent linker, T is a targeting molecule, D is a camptothecin-based drug, and q is any integer between 3 and 8. The drug conjugate may improve the poor water solubility, high toxicity and low bioavailability of camptothecin-based drugs.

## Claims

### Claim 1

A multi-branched drug conjugate having the following structural formula (III) or a pharmaceutically acceptable salt thereof:
wherein R is an organic core, POLY is polyethylene glycol, L is a multivalent linker, T is a targeting molecule, D is an active agent, and q is any integer between 3 and 8, wherein D is a camptothecin-based drug represented by the following formula:
wherein R1 to R5 are selected from the following groups independently from each other:
hydrogen, halogen, acyl, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, alkynyl, cycloalkyl, hydroxyl, cyano, nitro, azido, amido, hydrazine, amine group, substituted amine group, hydroxycarbonyl, alkoxycarbonyl, alkoxycarbonyloxy, carbamoyloxy, arylsulfonyloxy, and alkylsulfonyloxy; R6 is H or OR8; R8 is alkyl, alkenyl, cycloalkyl, halogenated alkyl, or hydroxyalkyl; and R7 is hydroxyl;
the multivalent linker L is:
symbol “*” represents an attachment point of the multivalent linker L and the targeting molecule T, “#” represents an attachment point of the multivalent linker L and the active agent D, “%” represents an attachment point of the multivalent linker L and POLY, wherein m and m′ are any integer between 1 and 20 respectively, and l and k are any integer between 1 and 10 respectively;
T is an “arginine-glycine-aspartic acid” sequence-containing RGD peptide, tLyp-1, Lyp-1, RPARPAR, Angiopep2, GE11, or folic acid.

### Claim 2 (depends on 1)

The multi-branched drug conjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein D is irinotecan, SN-38, 10-hydroxycamptothecin, or rubitecan.

### Claim 3 (depends on 1)

The multi-branched drug conjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein POLY is:
n is 5 to 500.

### Claim 4 (depends on 1)

The multi-branched drug conjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein the multivalent linker L is:

### Claim 5 (depends on 1)

The multi-branched drug conjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein T is iRGD or cRGD.

### Claim 6 (depends on 1)

The multi-branched drug conjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein said multi-branched drug conjugate has a structure represented by structural formula (IV), (V), or (VI):
wherein n is 5 to 500.

### Claim 7

A multi-branched drug conjugate having the following structure or a pharmaceutically acceptable salt thereof:

### Claim 8 (depends on 1)

A drug composition containing the multi-branched drug conjugate or a pharmaceutically acceptable salt thereof according to claim 1, and a pharmaceutically acceptable excipient.

### Claim 9 (depends on 1)

A method for treating colon cancer, lung cancer, breast cancer, ovarian cancer, pancreatic cancer, gastric cancer, brain glioma, and malignant sarcoma, cancer and lymphoma of breast, ovary, colon, kidney, bile duct, lung and brain, comprising administering to a subject in need thereof a therapeutic effective amount of the multi-branched drug conjugate or a pharmaceutically acceptable salt thereof according to claim 1.

### Claim 10

A preparation method of a multi-branched drug conjugate or a pharmaceutically acceptable salt thereof, comprising:
wherein R is an organic core, POLY is polyethylene glycol, L is a multivalent linker, T is a targeting molecule, D is an active agent, q is any integer between 3 and 8, and D is a camptothecin-based drug represented by the following formula:
wherein R1 to R5 are selected from the following groups independently from each other: hydrogen, halogen, acyl, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, alkynyl, cycloalkyl, hydroxyl, cyano, nitro, azido, amido, hydrazine, amine group, substituted amine group, hydroxycarbonyl, alkoxycarbonyl, alkoxycarbonyloxy, carbamoyloxy, aryl sulfonyloxy, and alkylsulfonyloxy; R6 is H or OR8; R8 is alkyl, alkenyl, cycloalkyl, halogenated alkyl, or hydroxyalkyl; and R7 is hydroxyl;
the multivalent linker L is:
symbol “*” represents an attachment point of the multivalent linker L and the targeting molecule T, “#” represents an attachment point of the multivalent linker L and the active agent D, “%” represents an attachment point of the multivalent linker L and POLY, wherein m and m′ are any integer between 1 and 20 respectively, and l and k are any integer between 1 and 10 respectively;
T is an “arginine-glycine-aspartic acid” sequence-containing RGD peptide, tLyp-1, Lyp-1, RPARPAR, Angiopep2, GE11, or folic acid;
(1) the active agent D is attached to the multivalent linker L to obtain a D-L portion;
(2) the D-L portion is attached to a multi-arm polymer RPOLY)q to obtain RPOLY-L-D)q; and
(3) RPOLY-L-D)q obtained in the previous step is attached to the targeting molecule T.

### Claim 11 (depends on 10)

A preparation method of the multi-branched drug conjugate or a pharmaceutically acceptable salt thereof according to claim 10, wherein D is irinotecan, SN-38, 10-hydroxycamptothecin, or rubitecan;
the multi-arm polymer RPOLY)q is 3armPEG20K-SCM, 4armPEG20K-SCM, or 8armPEG20K-SCM;
L is
symbol “*” represents an attachment point of the multivalent linker L and the targeting molecule T, “#” represents an attachment point of the multivalent linker L and the active agent D, and “%” represents an attachment point of the multivalent linker L and POLY; and
T is iRGD, cRGD, tLyp-1, Lyp-1, RPARPAR, Angiopep2, GE11, or folic acid.

### Claim 12 (depends on 1)

The multi-branched drug conjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein POLY is:
n is 50 to 200.

### Claim 13 (depends on 1)

The multi-branched drug conjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein POLY is:
n is 113.

### Claim 14 (depends on 1)

The multi-branched drug conjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein said multi-branched drug conjugate has a structure represented by structural formula (IV), (V), or (VI):
wherein n is 50 to 200.

### Claim 15 (depends on 1)

The multi-branched drug conjugate or a pharmaceutically acceptable salt thereof according to claim 1, wherein said multi-branched drug conjugate has a structure represented by structural formula (IV), (V), or (VI):
wherein n is 113.

### Claim 16 (depends on 7)

A drug composition containing the multi-branched drug conjugate or a pharmaceutically acceptable salt thereof according to claim 7, and a pharmaceutically acceptable excipient.

### Claim 17 (depends on 7)

A method for treating colon cancer, lung cancer, breast cancer, ovarian cancer, pancreatic cancer, gastric cancer, brain glioma, and malignant sarcoma, cancer and lymphoma of breast, ovary, colon, kidney, bile duct, lung and brain, comprising administering to a subject in need thereof a therapeutic effective amount of the multi-branched drug conjugate or a pharmaceutically acceptable salt thereof according to claim 7.